Glioblastoma (GBM) is a highly aggressive primary brain tumor characterized by poor prognosis. Conventional chemo-radiotherapy demonstrates limited therapeutic efficacy and is often accompanied by significant side effects, largely due to factors such as drug resistance, radiation resistance, the presence of the blood-brain barrier (BBB), and the activation of DNA damage repair mechanisms. There is a pressing need to enhance treatment efficacy, with BRD4 identified as a promising target for increasing GBM sensitivity to therapy. Lacking small molecule inhibitors, BRD4 can be degraded using PROteolysis Targeting Chimera (PROTAC), thereby inhibiting DNA damage repair. To deliver PROTAC, SIAIS171142 (SIS) effectively, we designed a responsive nanocapsule, MPL_(SS)P@SIS, featuring GBM-targeting and GSH-responsive drug release. Modified with 1-methyl-l-tryptophan (MLT), nanocapsules facilitate targeted delivery of SIS, downregulating BRD4 and sensitizing GBM cells to radiotherapy and chemotherapy. After intravenous administration, MPL_(SS)P@SIS selectively accumulates in tumor tissue, enhancing the effects of radiotherapy and temozolomide (TMZ) by increasing DNA damage and oxidative stress. GSH activates the nanocapsules, triggering BRD4 degradation and hindering DNA repair. In mouse models, the nanosensitizer, combined with TMZ and X-ray irradiation, efficiently inhibited the growth of GBM. These findings demonstrate a novel PROTAC-based sensitization strategy targeting BRD4, offering a promising approach for effective GBM therapy.

Objective To explore the prognostic value of glycolysis-related genes in colorectal cancer (CRC) patients and formulate a novel glycolysis-related prognostic risk model. Methods Single-cell and bulk transcriptomic data of CRC patients, along with clinical information, were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Glycolysis scores for each sample were calculated using single-sample Gene Set Enrichment Analysis (ssGSEA). Kaplan-Meier survival curves were generated to analyze the relationship between glycolysis scores and overall survival. Novel glycolysis-related subgroups were defined among the cell type with the highest glycolysis scores. Gene enrichment analysis, metabolic activity assessment, and univariate Cox regression were performed to explore the biological functions and prognostic impact of these subgroups. A prognostic risk model was built and validated based on genes significantly affecting the prognosis. Gene Set Enrichment Analysis (GSEA) was conducted to explore differences in biological processes between high- and low-risk groups. Differences in immune microenvironment and drug sensitivity between these groups were assessed using R packages. Potential targeted agents for prognostic risk genes were predicted using the Enrichr database. Results Tumor tissues showed significantly higher glycolysis scores than normal tissues, which was associated with a poor prognosis in CRC patients. The highest glycolysis score was observed in epithelial cells, within which we defined eight novel glycolysis-related cell subpopulations. Specifically, the P4HA1⁺ epithelial cell subpopulation was associated with a poor prognosis. Based on signature genes of this subpopulation, a six-gene prognostic risk model was formulated. GSEA revealed significant biological differences between high- and low-risk groups. Immune microenvironment analysis demonstrated that the high-risk group had increased infiltration of macrophages and tumor-associated fibroblasts, along with evident immune exclusion and suppression, while the low-risk group exhibited higher levels of B cell and T cell infiltration. Drug sensitivity analysis indicated that high-risk patients were more sensitive to Abiraterone, while low-risk patients responded to Cisplatin. Additionally, Valproic acid was predicted as a potential targeted agent. Conclusion High glycolytic activity is associated with a poor prognosis in CRC patients. The novel glycolysis-related prognostic risk model formulated in this study offers significant potential for enhancing the diagnosis and treatment of CRC.
Humans ; Colorectal Neoplasms/pathology* ; Glycolysis/genetics* ; Prognosis ; Transcriptome ; Tumor Microenvironment/genetics* ; Gene Expression Profiling ; Single-Cell Analysis ; Gene Expression Regulation, Neoplastic ; Male ; Female ; Kaplan-Meier Estimate

Objective:To study the changes in serum small molecule metabolites after brucella infection in humans using untargeted metabolomics methods, and screening representative biomarkers. Methods:A total of 109 serum samples collected from January 2019 to December 2021 at the Brucellosis Clinic of the Baotou Center for Disease Control and Prevention were divided into acute phase group ( n = 40), chronic phase group ( n = 35) of brucellosis, and healthy group ( n = 34) based on clinical diagnosis. Ultra-high performance liquid chromatography quadrupole time-of-flight mass spectrometry technology was used to test serum samples and screen for differential metabolites. Receiver operating characteristic curve was used to evaluate the predictive ability of differential metabolites for brucellosis. Enriched pathways were screened using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway to identify metabolic pathways significantly affected. Results:A total of 17 differential metabolites were screened between the acute phase group and the healthy group, and 12 differential metabolites were screened between the chronic phase group and the healthy group. There were a total of 5 differential metabolites (oleamide, linoleamide, stearamide, palmitoleic acid, α-linolenic acid) statistically significant among the three groups ( F = 16.84, 17.52, 14.31, 13.01, 20.76, P < 0.05). KEGG pathway analysis showed that the differential metabolites in the acute phase group were enriched in metabolic pathways such as ether lipid metabolism, glycerophosphate metabolism, sphingolipid signal and sphingolipid metabolism. The differential metabolites in the chronic phase group were enriched in metabolic pathways such as glycerophosphate metabolism, ether lipid metabolism, protein digestion and absorption metabolism. Conclusion:Untargeted metabolomics methods can screen out serum small molecule metabolites that undergo changes after brucella infection in the human body, including oleamide, linoleamide, stearamide, palmitoleic acid, α-linolenic acid can serve as potential biomarkers to distinguish brucellosis patients from healthy people.

Objective: To investigate the current situation and influencing factors of knowledge, attitude and practice (KAP) of fall prevention among the elderly in Huzhou City, Zhejiang Province, so as to provide the evidence for the development of fall intervention for the elderly. Methods: The permanent residents aged 60 years and over in Huzhou City were selected using multi-stratified cluster sampling method from March to April 2023. Demographic information, activity of daily living (ADL), fall risk, and KAP of fall prevention was collected using questionnaire surveys. Factors affecting KAP of fall prevention were identified using a multivariable logistic regression model. Results: Totally 2 160 questionnaires were allocated, and 2 104 valid questionnaires were recovered, with an effective recovery rate of 97.41%. There were 1 063 males (50.52%) and 1 041 females (49.48%), and 861 residents aged 60 to <70 years (40.92%). The awareness of fall prevention knowledge was 84.13%, the percentage of attitude towards fall prevention was 85.88%, and the percentage of practice of fall prevention was 14.59%. Multivariable logistic regression analysis showed that age, educational level, exercise duration and fall risk were associated with the awareness of fall prevention knowledge; age, educational level, marital status, exercise duration, ADL and fall risk were associated with the attitude towards fall prevention; gender, age, educational level, marital status, exercise duration, chronic diseases, ADL and fall risk were associated with the practice of fall prevention (all P<0.05). The desired access to fall prevention knowledge was mainly dominated by medical personnel, accounting for 75.51% (589/780). Conclusions The practice towards fall prevention among the elderly is relatively low in Huzhou City. The KAP of fall prevention is related to age, educational level, exercise duration and fall risk.

Poor ovarian response (POR) is a pathological condition in which the ovary responds poorly to gonadotropins,and is a major constraint on the unsatisfactory outcome of in vitro fertilization-embryo transfer (IVF-ET). Follicular growth,development,maturation,and expulsion are all affected by the yin-yang balance between heart and kidney,as well as the elevation exchange. If the heart and kidney essence and blood are insufficient,water and fire are out of harmony,and qi movement is not smooth,fewer high-quality follicles will be recruited and acquired during the ovarian stimulation cycle,resulting in a low transferable embryo rate and unacceptable pregnancy result. Sympathetic treatment of heart and kidney should be based on the following principles at different stages of the IVF-ET cycle:replenishing the heart,kidney,essence,and blood before entering the cycle,in order to nourish the essence and assist in the growth of the follicles;nourishing renal water,and clearing heart fire during the pituitary down-regulation period,in order to lessen the negative effects of the down-regulation medicinals;regulating the depression of the heart,liver,spleen,and kidney meridians during the follicle's retrieval period,in order to encourage the smooth release of the ova;and warming heart and kidney fire to improve endometrial tolerance during the implantation period. The application of the theory of intercourse of heart and kidney to elucidate the pathogenesis of POR is critical to the development of clinical strategies for fertility enhancement,as well as providing new ideas for the clinical application of traditional Chinese medicine in the field of reproduction.

Objective:To explore the clinical value of 18F-fluoromisonidazole (FMISO) PET/CT hypoxia imaging in early response to heavy ion radiotherapy in patients with non-small cell lung cancer(NSCLC). Methods:From April 2018 to January 2021, the 18F-FMISO PET/CT images of 23 NSCLC patients (19 males, 4 females; age (64.9±10.3) years) who received heavy ion radiotherapy in Shanghai Proton and Heavy Ion Center were retrospectively analyzed. The evaluation parameters included tumor volume (TV), tumor to background ratio (TBR) before and after radiotherapy. Patients were divided into hypoxia group and non-hypoxia group with the baseline TBR value≥1.4 as hypoxia threshold. Wilcoxon signed rank test was used to compare the differences of TV and TBR before and after radiotherapy in 2 groups. Results:Of 23 NSCLC patients, 17 were hypoxia and 6 were non-hypoxia. Compared with the baseline, TV after the radiotherapy (59.44(22.86, 99.43) and 33.78(8.68, 54.44) cm 3; z=-3.05, P=0.002) and TBR after the radiotherapy (2.25(2.09, 2.82) and 1.42(1.24, 1.67); z=-3.39, P=0.001) of the hypoxia group were significantly lower, while TV (16.19(6.74, 36.52) and 8.59(4.38, 25.47) cm 3; z=-1.57, P=0.120) and TBR (1.19(1.05, 1.27) and 1.10 (0.97, 1.14); z=-1.89, P=0.060) of the non-hypoxia group decreased with no significant differences. Conclusions:Hypoxic NSCLC tumors are sensitive to heavy ion radiation. Compared with non-hypoxic tumors, hypoxic tumors respond more quickly, and a significant reduction in TV can be observed early after radiotherapy. Heavy ion radiation can significantly improve tumor hypoxia.

Objective:To analyze the clinical features of severe refractory mycoplasma pneumoniae pneumonia (SRMPP) in children, and explore its risk factors complicated with extrapulmonary organ dysfunction.Methods:The clinical data of children with SRMPP who were admitted to the Department of Critical Care Medicine of Shanghai Children's Hospital from July 2017 to June 2019 were retrospectively summarized. The patients were divided into two groups according to the occurrence of extrapulmonary organ dysfunction: the extrapulmonary organ dysfunction group and the respiratory dysfunction group. The differences of clinical features and laboratory indexes between the two groups were compared, and the risk factors of extrapulmonary organ dysfunction were screened out by logistic regression analysis.Results:A total of 107 cases with SRMPP were admitted to the Pediatric Intensive Care Unit during the past two years, and there were 44 cases (41.1%) complicated with pleural effusion, 17 cases (15.9%) with plastic bronchitis, 104 cases (97.2%) with positive results for macrolide resistance genes (2063, 2064), with an in-hospital mortality rate of 2.8% (3/107). Among 107 children with SRMPP, there were 51 cases (47.7%) with extrapulmonary organ dysfunction, 43 cases (40.2%) with cardiovascular dysfunction, 13 cases (12.1%) with coagulation dysfunction, 11 cases (10.3%) with gastrointestinal dysfunction, 4 cases (3.7%) with renal dysfunction, 4 cases (3.7%) with brain dysfunction, 3 cases (2.8%) with liver dysfunction, and 16 cases (15.0%) with multiple organ dysfunction. Compared with the respiratory dysfunction group, the incidence of capillary leak syndrome was higher (52.9% vs. 17.9%, P < 0.001), the capillary leak index was increased [11.71 (4.63, 27.07) vs. 5.78 (2.07, 15.71), P =0.019], serum albumin was decreased [(32.2 ± 5.6)g/L vs. (34.7 ± 6.7)g/L, P=0. 041], and prothrombin time was prolonged significantly [12.7 (11.7, 13.8)s vs. 12.0 (11.4, 13.0)s, P=0. 009]. Logistic regression analysis showed that capillary leak syndrome ( OR=0. 278, 95% CI 0.102-0.759, P=0. 013) and prolonged prothrombin time ( OR=1. 443, 95% CI 1.018-2.046, P=0. 039) were independent risk factors for SRMPP complicated with extrapulmonary organ dysfunction. Conclusions:Approximately 50% of children with SRMPP have dysfunction of extrapulmonary organs, such as circulation, coagulation and gastrointestinal disorders. Capillary leak syndrome and prolonged prothrombin time are independent risk factors for SRMPP complicated with extrapulmonary organ dysfunction.

Objective:To explore the optimum time of ambulation of atrial fibrillation patients after radiofrequency ablation, to provide basis for patients' early postoperative rehabilitation.Methods:By convenient sampling method, a total of 120 patients with atrial fibrillation after radiofrequency ablation were collected at Yanghu Branch and City Branch of Changzhou Second People's Hospital from January 2020 to May 2021. They were divided into the early group, middle group and late group according to the random number table method, each group were 40 cases. All patients received routine postoperative intervention, the time of ambulation were 4, 6 and 12 h after operation in the early group, middle group and late group, respectively. The complication rate within 24 h after operation was compared among the three groups, and the comfort level of the three groups at 24, 48 and 72 h after operation was evaluated with Comfort Status Scale (GCQ).Results:Finally, 111 patients were included, including 37 in the early group, 38 in the middle group and 36 in the late group. There was no significant difference in the incidence of bleeding or hematoma, urinary retention, lumbago within 24 h after operation among the three groups ( P>0.05). The incidence of postural hypotension within 24 h after operation in the early group was 2.7% (1/37), which was lower than 21.1% (7/38) and 25.0% (9/36) in the middle and late groups, with a statistically significant difference ( χ2=4.86, 7.67, both P<0.05). At 48 and 72 h after operation, the scores of physiological dimension, psychological dimension and the total score of GCQ in the early group were (20.68 ± 3.07), (22.54 ± 3.35), (81.68 ± 6.11) and (22.54 ± 3.73), (24.38 ± 2.49), (84.92 ± 6.37), higher than those in the middle group (19.16 ± 2.19), (21.32 ± 2.27), (78.24 ± 5.58), (20.93 ± 2.85), (22.32 ± 2.04), (81.66 ± 6.56), and those in the late group (18.44 ± 1.50) (21.31 ± 1.99), (78.06 ± 4.32), (20.89 ± 2.25), (21.58 ± 1.86), (80.28 ± 6.44), the differences were statistically significant ( t values were 2.19-4.15, all P<0.05). Conclusions:Ambulation at 4 h after operation does not increase peripheral vascular complications, but can reduce the incidence of postural hypotension and improve the comfort of patients with atrial fibrillation after radiofrequency ablation.

Objective:Patients are breathing freely during adjuvant proton pencil beam radiotherapy after breast conserving surgery. Fluctuation of the thorax may affect the position of the end of the proton beam flow, which needs to be precisely evaluated on a millimeter scale.Methods:For 20 patients with breast cancer treated with proton radiotherapy after breast conserving surgery, PET-CT scan was performed approximately 10 min after the end of proton radiotherapy. The images of PET-CT were processed for ROI determination and sampling line (profile) extraction on a Raystation RV workstation to calculate the actual difference between the predicted and real radioactivity from the same spatial location as obtained by PET acquisition R50. Then, the differences in the spatial location between the actual process of proton irradiation and the planned process were obtained. Depth difference values for each pair of sampling lines were presented. Results:For 20 patients with breast cancer with a median follow-up of 22 months (range 12 - 46 months), all patients survived at the last follow-up, and no radiation pneumonitis was observed during the follow-up period. Among the verification results of 21 cases, the depth difference of evenly distributed was (-0.75±1.89) mm in the primary field and (-0.82±2.06) mm in the secondary field; The depth difference of sequential treatment was (1.81±1.87) mm in the primary field and (1.32±1.74) mm in the secondary field; The depth difference of synchronous addition in the primary field was (-1.47±1.44) mm, and the depth difference in the secondary field was (-1.48±2.11) mm.Conclusion:The results of off-line PET-CT in vivo biological verification show that the accuracy of the dose boundary cut-off was within 3 mm in breast cancer patients, which meets the clinical and physician requirement for the precision in breast cancer treatment.

BACKGROUND: Little was known about the association among time in range (TIR), time above range (TAR), time below range (TBR), and cancer mortality among patients with type 2 diabetes. We aimed to investigate the association among TIR, TAR, TBR, and the risk of cancer mortality among patients with type 2 diabetes. METHODS: A total of 6225 patients with type 2 diabetes were prospectively recruited in Shanghai, China. TIR was measured with continuous glucose monitoring at baseline and was defined as the average percentage of time in the target glucose range during a 24 h period. Cox proportion hazard regression analysis was used to determine the association between TIR and the risk of cancer mortality. RESULTS: During a mean follow-up of 7.10 years, we confirmed 237 death events related to cancer. The multivariable-adjusted hazard ratio (HR) for cancer mortality was 1.32 (95% confidence interval [CI]: 1.01-1.75) in patients with TIR ≤70% compared with those with TIR >70%. When TIR was considered as a continuous variable, the multivariable-adjusted HR for cancer mortality associated with each 10% decrease in TIR was 1.07 (95% CI: 1.02-1.14). In the site-specific analysis, a significant association between TIR as a continuous variable and the risk of hepatocellular cancer was found (HR: 1.24; 95% CI: 1.09-1.41). However, no relationship between hemoglobin A1c and cancer mortality was observed (HR: 1.04; 95% CI: 0.97-1.10). CONCLUSIONS The present study found an inverse association of TIR with the risk of cancer mortality among patients with type 2 diabetes. New evidence of TIR was added into the clinical practice that TIR may be an optimal target of glycemic control among patients with type 2 diabetes.
Blood Glucose ; Blood Glucose Self-Monitoring ; China ; Diabetes Mellitus, Type 2/complications* ; Humans ; Neoplasms ; Prospective Studies